Pyrimido[2,1-b][1,3]-thiazines

ABSTRACT

Novel 5H-thiazolo- and 5H-1,3,4-thiadiazolo[3,2-a]-pyrimidin-5-one and 3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3]-thiazin-6-one derivatives, which compounds are useful psychotropic agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of our copending application Ser. No.370,653, filed Apr. 21, 1982, now U.S. Pat. 4,443,451, which in turn isa continuation-in-part of application Ser. No. 283,590, filed July 15,1981, now abandoned.

BACKGROUND OF THE INVENTION

In Japanese Kokai No. 7 6146-497 and in Ann. Rep. Sankyo Res. Lab. 29,75-98 (1977) there are described a number of4H-pyrido[1,2-a]pyrimidin-4-one derivatives, bearing in the 3-positionan aminoalkyl substituent, wherein the amino group may be part of amorpholino-, a piperidino- or a piperazine moiety, which compounds aretaught to be useful as cardiovascular agents and as agents acting on thecentral nervous system.

In the European Patent application having the publication No. 37,265there are described a number of3-(1-piperidinylalkyl)-4H-pyrido[1,2-a]pyrimidin-4-one derivativeswherein the piperidine ring is substituted with an aroyl radical or afunctional derivative thereof, which compounds are potentserotonin-antagonists.

The compounds of the present invention differ from the prior artcompounds by the substitution of the 4H-pyrido[1,2-a]pyrimidin-4-onegroup by a 5H-thiazolo[3,2-a]pyrimidin-5-one, a5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one or a3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one group and by theiruseful properties in the treatment of psychotropic diseases.

DESCRIPTION OF THE PREFERRED EMBODIMENTS:

This invention is concerned with piperidine derivatives which arestructurally represented by the formula ##STR1## the pharmaceuticallyacceptable acid-addition salts and the stereochemically isomeric formsthereof, wherein:

R¹ is hydrogen, lower alkyl or Ar;

R² is hydrogen, lower alkyl or Ar;

R³ is hydrogen or lower alkyl;

Alk is a lower alkanediyl radical;

A is a bivalent radical having the formula ##STR2## having the carbonatom attached to the S-atom, wherein R⁴, R⁵ and R⁶ are eachindependently selected from the group consisting of hydrogen and loweralkyl and wherein R⁴ and R⁵ may also complete a saturated or unsaturated5- or 6-membered carbocyclic ring, optionally substituted with a loweralkyl radical; and

Q is a member selected from the group consisting of a radical having theformula --X--Ar (a) wherein X is a member selected from the groupconsisting of ##STR3## said R⁷ being hydrogen or lower alkyl and said qbeing the integer 2 or 3; and a radical having the formula ##STR4##wherein R⁸ is hydrogen or lower alkyl and R⁹, R¹⁰ and R¹¹ are eachindependently selected from the group consisting of hydrogen and halo;wherein Ar is phenyl or substituted phenyl, said substituted phenylbearing an amino group and/or 1,2 or 3 halo atoms.

As used in the foregoing definitions the term "halo" is generic tofluoro, chloro, bromo and iodo; "lower alkyl" is meant to includestraight and branched saturated hydrocarbon radicals, having from 1 to 6carbon atoms, such as, for example, methyl, ethyl, 1-methylethyl,1,1-dimethylethyl, propyl, butyl, pentyl, hexyl and the like; and "loweralkanediyl", as used in the definition of Alk, comprises straight andbranched saturated alkanediyl chains having from 1 to 4 carbon atoms.

Preferred compounds within the scope of formula (I) are those wherein R¹is lower alkyl.

More particularly preferred compounds within the scope of formula (I)are those wherein R¹ is lower alkyl, A is other than --CH₂ --CH₂ --CH₂--, Q is a radical of formula (a) wherein X is >C═O or a radical offormula (b) wherein R⁹, R¹⁰ and R¹¹ are hydrogen, Ar is other thanaminophenyl, R² is hydrogen or lower alkyl and R³ is hydrogen.

The most preferred compounds within the scope of formula (I) areselected from the group consisting of6-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one;6-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-oneand6-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one,the pharmaceutically acceptable acid addition salts and thestereochemically isomeric forms thereof.

The compounds of formula (I) can generally be prepared by reacting anappropriate reactive ester of formula (II) with an appropriatelysubstituted piperidine of formula (III). In the reactive ester (II) A,R¹ and Alk are as previously described and W represents a reactiveleaving group such as, for example, halo, particularly, chloro, bromoand iodo, or a sulfonyloxy group, e.g., methylsulfonyloxy,4-methylphenylsulfonyloxy and the like. In the piperidine (III) R², R³and Q are as previously described. ##STR5##

The foregoing reaction may be carried out following standardN-alkylating procedures. Said reaction is preferably carried out in anappropriate reaction-inert solvent such as, for example, a loweralkanol, e.g., methanol, ethanol, propanol, butanol and the likealkanols; an aromatic hydrocarbon, e.g., benzene, methylbenzene,dimethylbenzene, and the like; an ether, e.g., 1,4-dioxane,1,1'-oxybispropane and the like; a ketone, e.g., 4-methyl-2-pentanone;N,N-dimethylformamide; nitrobenzene; and the like. The addition of anappropriate base such as, for example, an alkali or earth alkaline metalcarbonate or hydrogen carbonate, may be utilized to pick up the acidwhich is liberated during the course of the reaction. A small amount ofan appropriate metal iodide, e.g., sodium or potassium iodide may beadded as a reaction promotor. Somewhat elevated temperatures areappropriate to enhance the rate of the reaction and preferably thereaction is carried out at the reflux temperature of the reactionmixture.

The compounds of formula (I) can also be prepared following art-knowncyclizing procedures for preparing pyrimidin-4-ones such as, forexample, by reacting an amine of formula (IV) with a cyclizing agent offormula (V) or by cyclizing a reagent of formula (VI) with an amine offormula (VII). ##STR6## In the formulas (IV), (V), (VI) and (VII) A, R¹,Alk, R², R³ and Q are as previously described and L represents anappropriate leaving group such as, for example, lower alkyloxy, hydroxy,halo, amino, mono- and di(lower alkyl)amino and the like.

The compounds of formula (I) can even so be prepared following art-knowncyclizing procedures for preparing thiazolo-, 1,3,5-thiadiazolo- anddihydrothiazine rings such as, for example, by cyclizing a2-mercaptopyrimidinone of formula (IX) with a reagent of formula(VIII-a) or, in case A is a --C(R⁴)═C(R⁵)-- radical, with a reagent offormula (VIII-b). ##STR7## In (VIII-a) W' has the same meaning aspreviously described for W.

The cyclization reaction wherein the compounds of formula (I) areprepared starting from (IV) and (V), (VI) and (VII), (VIII-a) and (IX)and (VIII-b) and (IX) may generally be carried out by stirring thereactants together, if desired, in the presence of a suitablereaction-inert solvent such as, for example, an aliphatic-, alicyclic-or aromatic hydrocarbon, e.g., hexane, cyclohexane, benzene and thelike; pyridine; N,N-dimethylformamide and the like amides. Elevatedtemperatures may be appropriate to enhance the reaction-rate. In somecases it may be preferable to carry out the reaction at the refluxtemperature of the reaction mixture.

Additionally, the compounds of formula (I) can also be prepared bycyclizing an intermediate of formula (VII) with an isothiocyanate offormula (X). ##STR8##

The foregoing cyclization reaction may be carried out following the sameprocedures as described for the preparation of (I) starting from (IV)and (V).

The compounds of formula (I) may also be converted into each otherfollowing art-known functional group-transformation procedures.

For example, the compounds of formula (I) wherein Ar--X-- is anoptionally substituted 2-aminobenzoyl radical, said compounds beingrepresented by the formula (I-a), may be prepared by the oxidativecleavage of the double bond in the compound of formula (I) wherein Q isa radical of formula (b), (I-b), and subsequent hydrolysis of the thusformed amide (XI). Said oxidative cleavage may be carried out, forexample, by the reaction of (I-b) with an appropriate oxidizing agent,such as, for example, sodium periodate in the presence of a catalyticamount of osmium tetroxide in a suitable solvent, e.g., 1,4-dioxane andthe like. The oxidation may equally well be carried out by bubblingozonized oxygen through a solution of (I-b) in acetic acid andsubsequently decomposing the intermediately formed ozonide with water.The thus obtained amidophenylcarbonyl intermediate (XI) is thenconverted into (I-a) by hydrolysis in acidic medium. ##STR9##

The compounds of formula (I) wherein X is a CHOH-- radical (I-c), maygenerally be derived from the corresponding aroyl compounds, (I-d), byreducing the carbonyl group of the latter with an appropriate reducingagent, e.g., sodium borohydride, sodium cyano borohydride and the likefollowing art-known methodologies. ##STR10## When, for example, sodiumborohydride is used as a reducing agent the reaction may conveniently becarried out in alkaline aqueous medium, if desired, in admixture with awater-miscible organic solvent such as, for example, an alicyclic ether,e.g., tetrahydrofuran, 1,4-dioxane and the like; or a lower alkanol,e.g., methanol, propanol and the like.

The compounds of formula (I) wherein X represents a radical>CH--O--C(O)--R⁷, wherein R⁷ has the previously defined meaning, (I-e),may be derived from the corresponding alcohols (I-c) by acylating thelatter with an appropriate acylating agent according to art-knownprocedures. Appropriate acylating agents which may be used for thispurpose include lower alkanoic acids and acyl halides and anhydridesderived therefrom. ##STR11##

The compounds of formula (I) wherein X is a methylene radical, (I-f),may be derived from the corresponding carbonyl derivatives, (I-d), bythe reduction of said carbonyl group to a methylene group, e.g., by theClemmensen reduction, using amalgated zinc and hydrochloric acid, or bythe Wolff-Kishner reduction, using hydrazine and alkali in ahigh-boiling polar solvent, such as, 1,2-ethanediol and the like.##STR12##

The compounds of formula (I) wherein X is ##STR13## wherein said q is aspreviously described, may be derived from the corresponding carbonylcompounds by subjecting the latter to a ketalization-reaction followingmethodologies generally known in the art. Cyclic lower alkylene ketals,for example, may be prepared following methodologies analogous to thosedescribed in Synthesis, 1974, (1) 23-26.

The compounds of formula (I) wherein X represents a radical of theformula >C═NOH or a radical of the formula >C═N-NH₂ can easily bederived from the corresponding carbonyl compounds by reacting the latterwith respectively hydroxylamine hydrochloride or hydrazine hydrochlorideaccording to art-known procedures of preparing oximes and hydrazones.

The compounds of formula (I) have basic properties and, consequently,they may be converted to their therapeutically active non-toxic additionsalt forms by treatment with appropriate acids, such as, for example,inorganic acids, such as hydrohalic acid, e.g., hydrochloric,hydrobromic and the like, and sulfuric acid, nitric acid, phosphoricacid and the like; or organic acids, such as, for example, acetic,propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic,propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic,2-hydroxybutanedioic, 2,3-dihydroxybutanedioic,2-hydroxy-1,2,3-propanetricarboxylic, benzoic, 3-phenyl-2-propenoic,α-hydroxybenzeneacetic, methanesulfonic, ethanesulfonic,benzenesulfonic, 4-methylbenzensulfonic, cyclohexanesulfamic,2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.Conversely the salt form can be converted by treatment with alkali intothe free base form.

It is obvious from formula (I) that the compounds of the presentinvention may exist under different stereochemically isomeric forms.

The compounds of formula (I) wherein Q is a radical of formula (a), Xbeing >CH--OH or >CH--O--C(O)--R⁷, have at least one chiral center intheir structure. This chiral center may be present in a R- and aS-configuration, this R- and S-notation being in correspondence with therules described in R. S. Cahn, C. Ingold and V. Prelog in Angew. Chem.Int. Ed. Engl., 5, 385, 511 (1966). Consequently, the compounds offormula (I) may be present in two different enantiomeric forms, whichmay be separated from each other, for example, by converting the mixtureof enantiomers into the acid addition salt form thereof with anoptically active acid, separating the diastereomeric salts, e.g., byselective crystallization, and liberating the pure enantiomers bytreatment with alkali.

When R³ is other than hydrogen the piperidine ring has two asymmetriccarbon atoms and each of those chiral centers may be present in a R- andS-configuration and the compounds of formula (I) may have differentdiastereochemical forms, resulting in a cis- and trans-configuration ofthe substituents on the piperidine moiety, which may be separated fromeach other by physical separation methods such as, selectivecrystallization and chromatographic techniques, e.g., counter currentdistribution, column-chromatography and the like techniques.

Pure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occurs stereospecificallyor highly stereoselectively.

Stereochemically isomeric forms of the compounds of formula (I) arenaturally intended to be embraced within the scope of the invention.

A number of the intermediates and starting materials used in theforegoing preparations are known compounds, others may be preparedaccording to art-known methodologies of preparing similar compounds andfor some of them synthetic methods are presented hereinafter.

The intermediates of formula (II) can be prepared by converting thehydroxyl function of the corresponding alcohols (XII) into a reactiveleaving group, e.g., by reacting the alcohols (XII) with thionylchloride, sulfuryl chloride, phosphor pentabromide, phosphoryl chloride,methanesulfonyl chloride, 4-methylbenzenesulfonyl chloride and the like.##STR14##

The alcohols (XII), used as starting materials herein, may be preparedfollowing cyclization procedures which are analogous to those describedhereinabove for the preparation of (I) starting from (IV) and (V), (VI)and (VII), (VIII-a) and (IX), (VIII-b) and (IX) or (X) and (VII). Saidcyclization reactions starting from (IV) and (XIII), (VI) and (XIV),(VIII-a) and (XV), (VIII-b) and (XV) and (X) and (XIV) are representedin scheme 1. ##STR15##

The intermediates of formula (II) wherein W is halo, said intermediatesbeing represented by the formula ##STR16## can also be derived from (IV)and (XIII), or (VI) and (XIV), or (VIII-a) or (VIII-b) and (XV), or (X)and (XIV) in a direct way, by stirring and, if desired, heating thereactants in a suitable solvent in the presence of a suitablehalogenating agent, e.g., phosphoryl chloride, thionyl chloride,phosphorpentabromide and the like. Optionally, said cyclizing andhalogenating reaction can be carried out in acidic medium, e.g., in thepresence of hydrogen chloride, 4-methylphenylsulfonic acid and the likeacids.

The intermediates of formula (V), (VII), (XIII) and (XIV) can be derivedfrom a compound having the formula (XVI), as shown in scheme 2.##STR17##

The intermediates of formula (V) can be prepared by stirring and, ifdesired, heating (XVI) with (XVIII) in the presence of a strong base,e.g., sodium hydride, sodium methoxide and the like in a suitablesolvent. The intermediates of formula (V) can also be prepared byreacting (XVI) with a reagent of formula W--Alk--W, as described for thereaction of (XVI) with (XVIII) and, subsequently, reacting the thusobtained (XVII) with (III) following art-known N-alkylating procedures.The intermediates of formula (XVII) may also be prepared by reacting(XVI) with a reagent of formula W--Alk--OH, as described for thereaction of (XVI) with (XVIII) and, subsequently, converting thehydroxyl function in the thus obtained (XIII) into a reactive leavinggroup, as described hereinabove.

The intermediates of formula (XIV) and the intermediates of formula(VII) can be derived from (XIII) respectively (V) by converting thecarbonyl function into an imine function, which imine may be inequilibrium with its tautomeric form.

The compounds of formula (I) and the pharmaceutical acceptable acidaddition salts thereof are potent antagonists of a series ofneurotransmittors and as a result they have useful pharmacologicalproperties. For example, the compounds of formula (I) and theirpharmaceutically acceptable acid addition salts possess strongpsychotropic acitivity, antihistamine activity and antiserotonineactivity.

The activity of the subject compounds as psychotropic agents isevidenced by the experimental data obtained in at least one of twodifferent test procedures, viz., the combined apomorphine-, tryptamine-and norepinephrine tests in rats and the apomorphine test in dogs. Thetests are carried out following the procedures described hereafter andthe experimental data are summarized in table 1.

The combined apomorphine (APO)-, tryptamine (TRY)- and norepinephrine(NOR) test in rats

The experimental animals used in this test were adult male Wistar rats(weight 240±10 g). After an overnight fast, the animals were treatedsubcutaneously (1 ml/100 g) with an aqueous solution of the compoundunder investigation (time=zero) and put in isolated observation cages.Thirty minutes thereafter (time=30 minutes) 1.25 mg/kg of apomorphinehydrochloride (APO) was injected intravenously and the rats wereobserved over a 1 hour period for the presence or absence of thefollowing apomorphine-induced phenomena: agitation and stereotypicchewing. At the end of this 1 hour period (time=90 minutes) the sameanimals were injected intravenously with 40 mg/kg of tryptamine (TRY)and the presence of the typical tryptamine-induced bilateral tonicseizures was noted. Two hours after pretreatment (time=120 minutes)finally, the same animals were challenged with 1.25 mg/kg intravenouslyof norepinephrine (NOR) and possible mortality was looked for up to 60minutes later.

The table 1 gives the ED₅₀ -values of a number of the compounds underconsideration. As used herein, the ED₅₀ -value represents the dose whichprotects 50% of the animals from apomorphine-, tryptamine- ornorepinephrine-induced phenomena.

The apomorphine test in dogs (APO-dog)

The method used is described by P. A. J. Janssen and C. J. E. Niemegeersin Arzneim.-Forsch. (Drug Res.), 9, 765-767 (1959).

The compounds listed in table 1 were administered subcutaneously tobeagle dogs at different doses and the animals were challenged 1 hourthereafter with a standard dose of 0.31 mg/kg (subcutaneous) ofapomorphine.

The table 1 gives the ED₅₀ -values of a number of the compounds underconsideration. As used herein, the ED₅₀ -value represents the dose whichprotects 50% of the animals from emesis.

The compounds listed in table 1 are not given for the purpose oflimiting the invention thereto but only to exemplify the usefulpharmacological activities of all the compounds within the scope offormula (I).

                                      TABLE 1                                     __________________________________________________________________________     ##STR18##                                                                                              Base                                                                              ED.sub.50 (APO)-rat                                                                   ED.sub.50 (TRY)                                                                       ED.sub.50 (NOR)                                                                       ED.sub.50 (APO)-dog                                                           5                                                 or  in mg/kg                                                                              in mg/kg                                                                              in mg/kg                                                                              in mg/kg                SA         R.sup.2                                                                           Q          Salt                                                                              s.c.    s.c.    s.c.    s.c.                    __________________________________________________________________________     ##STR19## H   4-FC.sub.6 H.sub.4CO                                                                     base                                                                              0.16     0.005  1.25    0.06                    SHCCH      H   4-FC.sub.6 H.sub.4CO                                                                     base                                                                              0.02    0.01    0.63    0.015                    ##STR20## H   4-FC.sub.6 H.sub.4CO                                                                     base                                                                              5.0     0.02    0.31    1.8                      ##STR21## H   4-FC.sub.6 H.sub.4CO                                                                     base                                                                              2.5     0.31    0.63    0.50                    SCH.sub.2CH.sub.2                                                                        H   4-FC.sub.6 H.sub.4CO                                                                     base                                                                              0.31    0.16    0.63    0.03                     ##STR22## H   4-FC.sub.6 H.sub.4CO                                                                     base                                                                              1.25    0.31    0.63    0.25                    SCHCH      CH.sub.3                                                                          4-FC.sub.6 H.sub.4CO                                                                     HCl 0.63    0.16    1.25    0.25                     ##STR23## H   1Hindol-3-yl                                                                             base                                                                              0.08    0.04    0.16    0.004                   SCHCH      H   1Hindol-3-yl                                                                             base                                                                              0.08    0.08    0.31    0.08                     ##STR24## H   1Hindol-3-yl                                                                             base                                                                              1.25    0.31    0.16    0.06                     ##STR25## H   1Hindol-3-yl                                                                             base                                                                              5.0     1.25    0.63    0.06                    SCH.sub.2CH.sub.2                                                                        H   1Hindol-3-yl                                                                             base                                                                              1.25    1.25    1.25    0.008                    ##STR26## H   1Hindol-3-yl                                                                             base                                                                              0.63    0.16    0.31    0.03                    SCHC(CH.sub.3)                                                                           H   5-F1Hindol-3-yl                                                                          base                                                                              1.25    0.63    --      0.12                    SCHCH      H   5-Cl1Hindol-3-yl                                                                         base                                                                              0.63    1.25    1.25    --                      SCHCH      H   5-F1Hindol-3-yl                                                                          base                                                                              1.25    0.31    1.25    0.12                    SCH.sub.2 CH.sub.2 CH.sub.2                                                              H   4-FC.sub.6 H.sub.4CO                                                                     base                                                                              0.31    0.63    1.25    0.03                    SCH.sub.2 CH.sub.2 CH.sub.2                                                              H   1Hindol-3-yl                                                                             base                                                                              0.63    0.63    1.25    0.015                    ##STR27## H   4-FC.sub.6 H.sub.4CO                                                                     base                                                                              0.63    0.04    0.63    0.12                     ##STR28## H   1Hindol-3-yl                                                                             base                                                                              0.31    0.16    0.63    0.015                   __________________________________________________________________________

The potency of the subject compounds as serotoninantagonists is clearlyevidenced by the results obtained in the following tests wherein theantagonistic activity of the subject compounds on the effect ofserotonin is examined.

Effects in gastric lesion tests: lesions induced by compound 48/80

Compound 48/80 (a mixture of oligomers obtained by condensation of4-methoxy-N-methylbenzeneethanamine and formaldehyde) is a potentreleaser of vasoactive amines from endogenous stores such as, forexample, histamine and serotonin. Rats injected with compound 48/80exhibit consistent changes of blood flow in different vascular beds:cyanosis of the ears and the extremities are prominent within fiveminutes after injection of the compound; the rats die from shock within30 minutes. The shock, followed by dead, can be avoided if the rats arepretreated with a classical H1 antagonist. However the stimulatoryeffects on gastric secretion are not suppressed so that rats treatedwith compound 48/80 and protected from shock by an H1 antagonist mayexhibit all signs of intensive gastric gland activity: gross autopsyshows distended stomachs with abnormal contents and rough bright redpatches all over the mucosa, corresponding to areas of disintegratedglands. A number of known serotonin antagonists such as, for example,methysergide, cyproheptadine, cinanserin, mianserin, pipamperone,spiperone, pizotifen and metergoline, prevent completely the cyanosis ofears and extremities as well as the lesions in the glandular area of thestomach and the abnormal gastric distension. Table 2 shows for a numberof compounds of formula (I) the doses (in mg/kg body weight) at whichthe distension of the stomach was completely absent in 50% of the testrats (ED₅₀ -values).

Antagonistic activity on the effect of serotonin on the caudal artery ofthe rat

Caudal arteries from fasted male rats (210-235 g) were used in the test.Two helical strips having a length of 5-6 cm and a width of 2 mm. wereobtained from each artery and mounted vertically in a 100 ml organ bathcontaining an oxygenated Krebs-Henseleit solution. Submaximalcontractions of the arterial strips were produced by adding single dosesof serotonin (40 ng/ml) to the organ bath for 2 minutes with each timean interval of 10 minutes. The amplitude of the contraction was measuredbefore and 5 minutes after adding the drug. After washing out, theagonist was added again three times in order to see whether thecontraction was restored and normalized.

Table 2 shows the ED₅₀ -values in ng/ml for a number of compounds offormula (I) and their pharmaceutically acceptable acid addition salts inthe above test. In this connection the ED₅₀ -values are the minimalconcentrations of the concerned drugs which reduce the amplitude of thecontraction to at least 50% of its normal value.

Inhibition of serotonin-induced contraction of guinea-pig trachea

Tracheal rings, 5 mm. long, from guinea-pigs (400-500 g, fastedovernight) were suspended with a preload of 2 g in a 100 ml tyrode-bath,gassed with a 95% O₂ and 5% CO₂ mixture (33° C.). Contractions wererecorded isometrically (Statham UC2, JSI transducer amplifier, Kipp BD-9penrecorder). A bolus of serotonin (0.31 mg/1, contact time 8 min.) wasadded to the bath fluid at 30 min. intervals, before and after a 30 min.incubation period with a single concentration of the antagonist. Theresponse to the agonist in presence of the antagonist was compared withthe response before the antagonist was added. (The preparation appearedunsuitable for time-activity studies). The ED₅₀ -values, as shown inTable 2, represent the concentrations of the antagonist which reducesthe effect of the agonist by 50%.

The potency of the subject compounds as histamineantagonists isevidenced by the results obtained in the following test wherein theantagonistic activity of the subject compounds on the effect ofhistamine is examined.

Protection of rats from compound 48/80-induced lethality

Compound 48/80, a mixture of oligomers obtained by condensation of4-methoxy-N-methyl-phenethylamine and formaldehyde has been described asa potent histamine releasing agent (Int. Arch. Allergy, 13, 336 (1958)).The protection from compound 48/80-induced lethal circulatory collapseappears to be a simple way of evaluating quantitatively theantihistaminic activity of test-compounds. Male rats of an inbred Wistarstrain, weighing 240-260 g were used in the experiment. After overnightstarvation the rats were transferred to conditioned laboratories(temp.=21±1° C., relative humidity =65±5%).

The rats were treated subcutaneously or orally with a test compound orwith the solvent (NaCl solution, 0.9%). One hour after treatment therewas injected intravenously compound 48/80, freshly dissolved in water,at a dose of 0.5 mg/kg (0.2 ml/100 g of body weight).

In control experiments, wherein 250 solvent-treated animals wereinjected with the standard dose of compound 48/80 not more than 2.8% ofthe animals survived after 4 hours, is therefore considered to be a safecriterion of a protective effect of drug administration.

Table 2 shows the ED₅₀ -values in mg/kg for a number of compounds offormula (I) and their pharmaceutically acceptable acid addition salts inthe above test. In this connection the ED₅₀ -values are the minimaldoses of the concerned compounds, administered in the subcutaneous way,whereby 50% of the rats are protected against compound 48/80-inducedlethality.

The compounds listed in table 2 are not given for the purpose oflimiting the scope of the invention but only to exemplify the usefulpharmacological activities of all the compounds within the scope offormula (I).

                                      TABLE 2                                     __________________________________________________________________________     ##STR29##                                                                                                           caudal artery                                                      Base                                                                             gastric rat                                                                or lesion test                                                                           ED.sub.50                                                                            guinea pig                                                                             48/80-test             SA         R.sup.2                                                                          R.sup.3                                                                          Q          Salt                                                                             ED.sub.50 in mg/kg                                                                    in ng/ml                                                                             ED.sub.50 in                                                                           ED.sub.50 in           __________________________________________________________________________                                                           mg/kg                   ##STR30## H  H  4-FC.sub.6 H.sub.4CO                                                                     base                                                                             0.01    0.32   0.32     0.31                   SCHCH      H  H  4-FC.sub.6 H.sub.4CO                                                                     base                                                                             0.005   0.14   0.18     0.31                    ##STR31## H  H  4-FC.sub.6 H.sub.4CO                                                                     base                                                                             0.08    0.14   5        0.16                    ##STR32## H  H  4-FC.sub.6 H.sub.4CO                                                                     base                                                                             0.0025  1.25   0.08     0.16                   SCH.sub.2CH.sub.2                                                                        H  H  4-FC.sub.6 H.sub.4CO                                                                     base                                                                             0.0005  0.32   0.16     0.63                    ##STR33## H  H  4-FC.sub.6 H.sub.4CO                                                                     base                                                                             0.04    0.32   0.32     0.31                   SCHCH      CH.sub.3                                                                         H  4-FC.sub.6 H.sub.4CO                                                                     HCl                                                                              0.005   0.32   <2.5     0.16                    ##STR34## H  H  1Hindol-3-yl                                                                             base                                                                             0.0025  0.14   0.63     0.08                   SCHCH      H  H  1Hindol-3-yl                                                                             base                                                                             0.08    0.08   0.16     0.02                    ##STR35## H  H  1Hindol-3-yl                                                                             base                                                                             0.04    0.32   5        0.63                    ##STR36## H  H  1Hindol-3-yl                                                                             base                                                                             0.04    0.56   <0.63    0.04                   SCH.sub.2CH.sub.2                                                                        H  H  1Hindol-3-yl                                                                             base                                                                             0.04    0.31   0.31     0.02                    ##STR37## H  H  1Hindol-3-yl                                                                             base                                                                             0.31    0.31   1.25     0.08                   SCHC(CH.sub.3)                                                                           H  H  5-F1Hindol-3-yl                                                                          base                                                                             0.31    0.31   --       0.63                   SCHCH      H  H  5-Cl1Hindol-3-yl                                                                         base                                                                             1.25    --     --       2.5                    SCHCH      C.sub.6 H.sub.5                                                                  H  4-FC.sub.6 H.sub.4CO                                                                     base                                                                             2.5     --     --       --                     SCHCH      H  H  5-F1Hindol-3-yl                                                                          base                                                                             0.08    1.25   --       1.25                   SCH.sub.2 CH.sub.2 CH.sub.2                                                              H  H  4-FC.sub.6 H.sub.4CO                                                                     base                                                                             0.01    0.32   --       0.16                   SCH.sub.2 CH.sub.2 CH.sub.2                                                              H  H  1Hindol-3-yl                                                                             base                                                                             0.02    0.32   <0.63    0.04                   SCH.sub.2 CH.sub.2                                                                       H  CH.sub.3                                                                         1Hindol-3-yl                                                                             base                                                                             2.5     --     --       2.5                     ##STR38## H  H  4-FC.sub.6 H.sub.4CO                                                                     base                                                                             0.01    --     --       0.08                    ##STR39## H  H  1Hindol-3-yl                                                                             base                                                                             0.16    0.32   --       0.04                   __________________________________________________________________________

Due to their pharmacological activities the compounds of formula (I) andtheir pharmaceutically acceptable acid addition salts can be used in thetreatment of psychotropic diseases and in the treatment of a variety ofcomplaints in which serotonin release is of predominnt importance suchas, for example, in the blocking of serotonin-induced contractions ofbronchial tissues and of blood vessels, arteries as well as veins. Thesubject compounds have also useful properties as sedating-, anxiolytic-,anti-agressive-, anti-stress-, muscular protectant- and cardiovascularprotectant agents and, consequently, they are useful to protectwarm-blooded animals, for example, in stress situations, e.g., duringtransport periods and the like situations. Additionally, the subjectcompounds are useful as protectors of endotoxine shocks and asantidiarrhoeals.

In view of their useful pharmacological properties the subject compoundsmay be formulated into various pharmaceutical forms for administrationpurposes. To prepare the pharmaceutical compositions of this invention,a pharmaceutically effective amount of the particular compound, in baseor acid-addition salt form, as the active ingredient is combined inintimate admixture with a pharmaceutically acceptable carrier, whichcarrier may take a wide variety of forms depending on the form ofpreparation desired for administration. These pharmaceuticalcompositions are desirable in unitary dosage form suitable, preferably,for administration orally, rectally or by parenteral injection. Forexample, in preparing the compositions in oral dosage form, any of theusual pharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions; orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of their ease in administration, tabletsand capsules represent the most advantageous oral dosage unit form, inwhich case solid pharmaceutical carriers are obviously employed. Forparenteral compositions, the carrier will usually comprise sterilewater, at least in large part, though other ingredients, for example, toaid solubility, may be included. Injectable solutions, for example, maybe prepared in which the carrier comprises saline solution, glucosesolution or a mixture of saline and glucose solution. Injectablesuspensions may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed. Acid additionsalts of (I), due to their increased water solubility over thecorresponding base form, are obviously more suitable in the preparationof aqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

The following formulations exemplify typical pharmaceutical compositionsin dosage unit form suitable for systemic administration to animal andhuman subjects in accordance with the present invention. These examplesare given to illustrate and not to limit the scope of the presentinvention.

Oral Drops

The following formulation provides 50 liters of an oral-drop solutioncomprising 10 mg of6-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-oneas the active ingredient (A.I.) per milliliter.

    ______________________________________                                        A.I.                  500    grams                                            2-hydroxypropanoic acid                                                                             0.5    liters                                           sodium saccharin      1750   grams                                            cocoa flavor          2.5    liters                                           purified water        2.5    liters                                           polyethylene glycol q.s. aq                                                                         50     liters                                           ______________________________________                                    

The A.I. was dissolved in the 2-hydroxypropanoic acid and 1.5 liters ofthe polyethylene glycol at 60°-80° C. After cooling to 30°-40° C. therewere added 35 liters of polyethylene glycol and the mixture was stirredwell. Then there was added a solution of the sodium saccharin in 2.5liters of purified water and while stirring there were added the cocoaflavor and polyethylene glycol q.s. ad volume. The resulting solutionwas filled into suitable containers.

Oral Solution

The following formulation provides 20 liters of an oral solutioncomprising 20 mg of6-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-oneas the active ingredient (A.I.) per teaspoonful (5 milliliters).

    ______________________________________                                        A.I.                  20    grams                                             2,3-dihydroxybutanedioic                                                                            10    grams                                             acid                                                                          sodium saccharin      40    grams                                             1,2,3-propanetriol    12    liters                                            Sorbitol 70% solution 3     liters                                            Methyl 4-hydroxybenzoate                                                                            9     grams                                             Propyl 4-hydroxybenzoate                                                                            1     gram                                              Raspberry essence     2     milliliters                                       Gooseberry essence    2     milliliters                                       Purified water q.s. ad                                                                              20    liters.                                           ______________________________________                                    

The methyl and propyl 4-hydroxybenzoates were dissolved in 4 liters ofboiling purified water. In 3 liters of this solution were dissolvedfirst the 2,3-dihydroxybutanedioic acid and thereafter the A.I.. Thelatter solution was combined with the remaining part of the formersolution and the 1,2,3-propanetriol and the sorbitol solution were addedthereto. The sodium saccharin was dissolved in 0.5 liters of water andthe raspberry and gooseberry essences were added. The latter solutionwas combined with the former, water was added q.s. ad volume and theresulting solution was filled in suitable containers.

Capsules

The following formulation provides 1000 capsules comprising each 20 mgof6-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-oneas the active ingredient (A.I.).

    ______________________________________                                        A.I.                   20    grams                                            Sodium lauryl sulfate  6     grams                                            Starch                 56    grams                                            Lactose                56    grams                                            Colloidal silicon dioxide                                                                            0.8   grams                                            Magnesium stearate     1.2   grams                                            ______________________________________                                    

The composition was prepared by stirring the ingredients vigorouslytogether. The resulting mixture was subsequently filled into suitablehardened gelatine capsules.

Film-Coated Tablets

10.000 compressed tablets, each containing as the active ingredient 10mg of6-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,3-dihydro-7-methyl-5H-thiazolo-[3,2-a]pyrimidin-5-one,were prepared from the following formulation:

    ______________________________________                                        Tablet core:                                                                  A.I.                   100    grams                                           Lactose                570    grams                                           Starch                 200    grams                                           Polyvinylpyrrolidone   10     grams                                           (Kollidon-K 90)                                                               Microcrystalline cellulose                                                                           100    grams                                           (Avicel)                                                                      Sodium dodecyl sulfate 5      grams                                           Hydrogenated vegetable oil                                                                           15     grams                                           (Sterotex)                                                                    Coating:                                                                      Methyl cellulose (Methocel 60 HG)                                                                    10     grams                                           Ethyl cellulose (Ethocel 22 cps)                                                                     5      grams                                           1,2,3-propanetriol     2.5    milliliters                                     Polyethylene glycol 6000                                                                             10     grams                                           Concentrated colour suspension                                                                       30     milliliters                                     (Opaspray K-1-2109)                                                           Polyvinylpyrrolidone   5      grams                                           Magnesium octadecanoate                                                                              2.5    grams                                           ______________________________________                                    

Preparation of tablet core

A mixture of the A.I., the lactose and the starch was mixed well andthereafter humidified with a solution of the sodium dodecyl sulfate andthe polyvinylpyrrolidone in about 200 milliliters of water. The wetpowder mixture was sieved, dried and sieved again. Then there was addedthe microcrystalline cellulose and the hydrogenated vegetable oil. Thewhole was mixed well and compressed into tablets.

Coating

To a solution of the methyl cellulose in 75 milliliters of denaturatedethanol there was added a solution of the ethyl cellulose in 150milliliters of dichloromethane. Then there were added 75 milliliters ofdichloromethane and the 1,2,3-propanetriol. The polyethylene glycol wasmolten and dissolved in 75 milliliters of dichloromethane. The lattersolution was added to the former and then there were added the magnesiumoctadecanoate, the polyvinylpyrrolidone and the concentrated coloursuspension and the whole was homogenated.

The tablet cores were coated with the thus obtained mixture in a coatingapparatus.

Injectable Solution

The following formulation provides 1 liter of a parenteral solutioncomprising 4 mg of6-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-oneas the active ingredient (A.I.) per milliliter.

    ______________________________________                                        A.I.                  4      grams                                            Lactic acid           4      grams                                            Propylene glycol      0.05   grams                                            Methyl 4-hydroxybenzoate                                                                            1.8    grams                                            Propyl 4-hydroxybenzoate                                                                            0.2    grams                                            Purified water q.s. ad                                                                              1      liter.                                           ______________________________________                                    

The methyl and propyl 4-hydroxybenzoates were dissolved in about 0.5liters of boiling water for injection. After cooling to about 50° C.there were added while stirring the lactic acid, the propylene glycoland the A.I.. The solution was cooled to room temperature andsupplemented with water for injection q.s. ad volume. The solution wassterilized by filtration (U.S.P. XVII p. 811) and filled in sterilecontainers.

Suppositories

100 Suppositories each containing 20 mg of6-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-oneas the active ingredient (A.I.) were prepared from the followingformulations:

    ______________________________________                                        A.I.                   3      grams                                           2,3-Dihydroxybutanedioic acid                                                                        3      grams                                           Polyethylene glycol 400                                                                              25     milliliters                                     Surfactant (Span)      12     grams                                           Triglycerides (Witepsol 555) q.s. ad                                                                 300    grams.                                          ______________________________________                                    

The A.I. was dissolved in a solution of the 2,3-dihydroxybutanedioicacid in the polyethylene glycol 400. The surfactant and thetriglycerides were molten together. The latter mixture was mixed wellwith the former solution. The thus obtained mixture was poured ontomoulds at a temperature of 37°-38° C. to form the suppositories.

In view of the usefulness of the subject compounds in the treatment ofpsychotropic diseases it is evident that the present invention providesa method of treating warm-blooded animals suffering from psychotropicdiseases, said method comprising the systemic administration of apharmaceutically effective amount of a compound of formula (I), apharmaceutically acceptable acid addition salt or a stereochemicallyisomeric form thereof in admixture with a pharmaceutical carrier.

The following examples are intended to illustrate but not to limit thescope of the present invention. Unless otherwise stated all parts hereinare by weight and all temperatures are in the centigrade scale.

EXAMPLES A. Preparation of Intermediates EXAMPLE I

A mixture of 40 parts of 4-methyl-2-thiazolamine, 30 parts of3-acetyl-4,5-dihydro-2(3H)-furanone and 225 parts of methylbenzene wasstirred and refluxed for 2.50 hours with 0.6 parts of hydrochloric acid.After cooling to room temperature, 170 parts of phosphoryl chloride wereadded. The whole was heated slowly to about 110° C. and stirring wascontinued for 2 hours at this temperature. The reaction mixture wasevaporated and the residue was poured onto crushed ice. Ammoniumhydroxide was added till a pH of 8 was reached. The product wasextracted with trichloromethane. The extract was dried, filtered andevaporated. The residue was purified by column-chromatography oversilica gel using a mixture of trichloromethane and methanol (95:5 byvolume) as eluent. The pure fractions were collected and the eluent wasevaporated. The residue was crystallized from a mixture of2,2'-oxybispropane and 2-propanol, yielding 19.3 parts of6-(2-chloroethyl)-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5 -one(intermediate 1).

In a similar manner there were also prepared:

6-(2-chloroethyl)-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(intermediate 2); and

3-(2-chloroethyl)-7,8-dihydro-2-methyl-4H,6H-cyclopenta[4,5]thiazolo[3,2-a]pyrimidin-4-one;mp. 118° C. (intermediate 3).

EXAMPLE II

A mixture of 75 parts of 2-benzothiazolamine, 76 parts of3-acetyl-4,5-dihydro-2(3H)-furanone, 2,4 parts of a hydrochloric acidsolution 12N and 270 parts of methylbenzene was stirred and refluxed for2 hours using a water-separator. The reaction mixture was cooled and 323parts of phosphoryl chloride were added at a temperature between 20° and25° C. The whole was slowly heated to 110° C. and stirring was continuedfor 2 hours at this temperature. The solvent was evaporated and theresidue was poured onto a mixture of crushed ice and ammonium hydroxide.The product was extracted with trichloromethane. The extract was dried,filtered and evaporated. The residue was purified bycolumnchromatography over silica gel using a mixture of trichloromethaneand methanol (92:8 by volume) as eluent. The pure fractions werecollected and the eluent was evaporated. The residue was crystallizedfrom a mixture of 2-propanol and 2,2'-oxybispropane, yielding 39 partsof 3-(2-chloroethyl)-2-methyl-4H-pyrido[2,1-b]benzothiazol-4-one; mp.144° C. (intermediate 4).

In a similar manner there were also prepared:

6-(2-chloroethyl)-2,7-dimethyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one;mp. 118° C. (intermediate 5); and

6-(2-chloroethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(intermediate 6).

EXAMPLE III

A mixture of 30 parts of4-hydroxy-2-mercapto-6-methyl-5-pyrimidineethanol, 6.8 parts of sodiumhydroxide, 15 parts of sodium hydrogen carbonate and 100 parts of2-propanone was stirred at room temperature and there were added 180parts of tetrahydrofuran and 170 parts of water. Then there were addedat once 25 parts of 3-chloro-2-butanone and 0.2 parts ofN,N,N-triethylbenzeneethanaminium chloride and the whole was stirred andheated for 1 hour at 60° C. Stirring was continued overnight at roomtemperature. The reaction mixture was filtered and the filtrate wassalted out. The organic phase was separated, dried, filtered andevaporated, yielding 36 parts of5-(2-hydroxyethyl)-6-methyl-2-[(1-methyl-2-oxopropyl)thio]-4(3H-pyrimidinoneas an oily residue (intermediate 7).

EXAMPLE IV

A mixture of 30 parts of4-hydroxy-2-mercapto-6-methyl-5-pyrimidineethanol, 25 parts of potassiumcarbonate, 270 parts of N,N-dimethylacetamide and 75 parts of water wasstirred at room temperature and 36 parts of 1,3-dibromopropane wereadded at once: temperature rises to 50° C. The whole was stirredovernight at room temperature. The reaction mixture was evaporated andwater was added to the residue. The solid product was washed with waterand dried in vacuo at 100° C., yielding 21 parts (58%) of3,4-dihydro-7-(2-hydroxyethyl)-8-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one;mp. 155° C. (intermediate 8).

In a similar manner there was also prepared:

2,3-dihydro-6-(2-hydroxyethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;mp. 148.7° C. (intermediate 9).

EXAMPLE V

A mixture of 20 parts of3,4-dihydro-7-(2-hydroxyethyl)-8-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one,50 parts of acetic acid and 180 parts of a hydrobromic acid solution 67%in acetic acid was stirred and heated to reflux. Stirring was continuedovernight at reflux temperature. The reaction mixture was evaporated andthe solid residue was triturated in 2-propanone. The product wasfiltered off and dried, yielding 24 parts (100%) of7-(2-bromoethyl)-3,4-dihydro-8-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-onemonohydrobromide; mp. 215° C. (intermediate 10).

In a similar manner there was also prepared:

6-(2-bromoethyl)-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-onemonohydrobromide; mp. 237.2° C. (intermediate 11).

EXAMPLE VI

A mixture of 36 parts of5-(2-hydroxyethyl)-6-methyl-2-[(1-methyl-2-oxopropyl)thio]-4(3H)-pyrimidinoneand 240 parts of a hydrobromic acid solution 60% in acetic acid wasstirred and heated for 4 hours at 90° C. The reaction mixture wasevaporated and the residue was suspended in 400 parts of 2-propanone.The solid product was filtered off, washed with 2-propanone and dried,yielding 44 parts of6-(2-bromoethyl)-2,3,7-trimethyl-5H-thiazolo[3,2-a]pyrimidin-5-onemonohydrobromide; mp. 172° C. (intermediate 12).

EXAMPLE VII

To a stirred and refluxing Grignard-complex previously prepared startingfrom 14.6 parts of magnesium and 105 parts of 1-bromo-4-fluorobenzene in450 parts of 1,1'-oxybisethane, was added dropwise a solution of 94parts of 4-phenyl-1-(phenylmethyl)-4-piperidinecarbonitrilemonohydrochloride in 360 parts of methylbenzene. About 250 parts of1,1'-oxybisethane were distilled off at an internal temperature of60°-65° C. The turbid solution was stirred and refluxed for 5 hours. Thereaction mixture was decomposed with a saturate ammonium chloridesolution in water. The layers were separated and the organic phase wasdried, filtered and evaporated. The oily residue was boiled in a dilutehydrochloric acid solution. After cooling, the whole was alkalized withammonium hydroxide and extracted with trichloromethane. The extract wasdried, filtered and evaporated. The residue was crystallized from amixture of 2-propanol and 2,2'-oxybispropane, yielding 91 parts (81%) of(4-fluorophenyl) [4-phenyl-1-(phenylmethyl)-4-piperidinyl]methanone; mp.147.6° C. (intermediate 13).

Following the same Grignard-procedure there was also prepared:

(4-fluorophenyl)[4-methyl-1-(phenylmethyl)-4-piperidinyl]methanone as anoily residue (intermediate 14).

EXAMPLE VIII

To a stirred mixture of 79 parts of (4-fluorophenyl)[4-phenyl-1-(phenylmethyl)-4-piperidinyl]methanone and 630 parts ofmethylbenzene were added dropwise 32 parts of ethyl carbonochloridate atroom temperature. Upon completion, stirring was continued for 5 hours atreflux temperature. The reaction mixture was evaporated and the(chloromethyl)benzene was distilled in vacuo (pump). The oily residuewas purified by column-chromatography over silica gel using a mixture oftrichloromethane and methanol (98:2 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The residue wascrystallized from a mixture of 2,2'-oxybispropane and a small amount ofpetroleumether, yielding 35.5 parts of ethyl4-(4-fluorobenzoyl)-4-phenyl-1-piperidinecarboxylate; mp. 91.7° C.(intermediate 15).

In a similar manner there was also prepared:

ethyl 4-(4-fluorobenzoyl)-4-methyl-1-piperidinecarboxylate as a residue(intermediate 16).

EXAMPLE IX

A mixture of 14 parts of ethyl4-(4-fluorobenzoyl)-4-phenyl-1-piperidinecarboxylate and 150 parts of ahydrobromic acid solution 48% in water was stirred and refluxed for 30minutes. The reaction mixture was diluted with 100 parts of water andthe whole was stirred while the mixture was allowed to cool to roomtemperature. The precipitated product was filtered off (filtrate I wasset aside), washed with methylbenzene and stirred in 2-propanone. It wasfiltered off again (filtrate II was set aside) and dried, yielding afirst fraction of 4.3 parts of (4-fluorophenyl)(4-phenyl-4-piperidinyl)methanone hydrobromide hemihydrate.

Filtrates I and II were evaporated and the solid residue was stirred in4-methyl-2-pentanone. The product was filtered off and dried, yielding asecond fraction of 6.2 parts of (4-fluorophenyl)(4-phenyl-4-piperidinyl)methanone hydrobromide hemihydrate; mp. 173.4°C. Total yield: 73%. (intermediate 17).

In a similar manner there was also prepared:

(4-fluorophenyl) (4-methyl-4-piperidinyl)methanone hydrobromide(intermediate 18).

EXAMPLE X

To a stirred mixture of 100 parts of pyridine, 53 parts of5-fluoro-1H-indole and 270 parts of benzene were added dropwise 57 partsof benzoyl chloride. Upon completion, stirring was continued overnightat room temperature. The reaction mixture was poured onto a dilutehydrochloric acid solution and the layers were separated. The organicphase was dried, filtered and evaporated. The residue was purified twiceby column-chromatography over silica gel using a mixture oftrichloromethane and methanol (95:5 by volume) as eluent. The purefractions were collected and the eluent was evaporated, yielding 80parts of 1-benzoyl-4-(5-fluoro-1H-indol-3-yl)-1,4-dihydropyridine as aresidue (intermediate 19).

In a similar manner there was also prepared:

1-benzoyl-1,4-dihydro-4-(1H-indol-3-yl)-3-methylpyridine as an oilyresidue (intermediate 20).

EXAMPLE XI

A mixture of 65 parts of 1-benzoyl-4-(5-fluoro-1e,uns/H/-indol-3-yl)-1,4-dihydropyridine and 270 parts of N,N-dimethylacetamidewas hydrogenated at normal pressure and at room temperature with 10parts of palladium-on-charcoal catalyst 10%. After the calculated amountof hydrogen was taken up, the catalyst was filtered off and the filtratewas evaporated. The residue was poured onto water and the product wasextracted with 4-methyl-2-pentanone. The extract was dried, filtered andevaporated. The residue was purified by column-chromatography oversilica gel using a mixture of trichloromethane and methanol (95:5 byvolume) as eluent. The pure fractions were collected and the eluent wasevaporated, yielding 5 parts of1-benzoyl-4-(5-fluoro-1H-indol-3-yl)piperidine as a residue(intermediate 21).

In a similar manner there was also prepared:

cis-1-benzoyl-4-(1H-indol-3-yl)-3-methylpiperidine; mp. 230.7° C.(intermediate 22).

EXAMPLE XII

A mixture of 21 parts of cis-1-benzoyl-4-(1e,uns/H/-indol-3-yl)-3-methylpiperidine, 60 parts of potassium hydroxide 385parts of 1,2-ethanediol and 80 parts of water was stirred and refluxed(about 130° C.) overnight. After cooling for a while, about 200 parts ofwater were added whereupon the product was crystallized. The whole wasfurther cooled and the solid product was filtered off, washed with a lotof water and with 2,2'-oxybispropane and dried, yielding 11.2 parts(80%) of cis-3-(3-methyl-4-piperidinyl)-1H-indole (intermediate 23).

In a similar manner there was also prepared:

5-fluoro-3-(4-piperidinyl)-1H-indole (intermediate 24).

B. PREPARATION OF FINAL COMPOUNDS EXAMPLE XIII

A mixture of 3.3 parts of6-(2-chloroethyl)-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one,3 parts of (4-fluorophenyl) (4-piperidinyl)methanone hydrochloride, 8parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone wasstirred and refluxed for 20 hours using a water-separator. The reactionmixture was filtered hot over Hyflo and the filter-cake was washed withtrichloromethane. The filtrate was evaporated. The residue was purifiedby column-chromatography over silica gel using a mixture oftrichloromethane and methanol (95:5 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The residue wascrystallized from a mixture of 2-propanone and 2,2'-oxybispropane,yielding 2 parts of6-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;mp. 165.6° C. (compound 1).

In a similar manner there were also prepared:

7-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]3,4-dihydro-8-methyl-2H,6H-pyrimido[2,1-b[1,3]thiazin-6-one; mp. 165.2° C. (compound 2); and

3,4-dihydro-7-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-8-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one;mp. 227.1° C. (compound 3).

EXAMPLE XIV

A mixture of 3.75 parts of6-(2-chloroethyl)-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5 -one, 3.6parts of (4-fluorophenyl) (4-piperidinyl)methanone hydrochloride, 12parts of sodium carbonate, 0.1 parts of potassium iodide and 200 partsof 4-methyl-2-pentanone was stirred and refluxed for 22 hours using awater-separator. The reaction mixture was filtered hot over Hyflo andthe filtrate was evaporated. The residue was purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and methanol (90:10 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The residue wascrystallized from a mixture of acetonitrile and 2,2'-oxybispropane,yielding 5 parts of6-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one;mp. 199.7° C. (compound 4).

Following the same procedure and using equivalent amounts of theappropriate starting materials there were also prepared:

6-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;mp. 147.9° C. (compound 5);

3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2-methyl-4e,uns/H/-pyrimido[2,1-]benzothiazol-4-one; mp. 175.4° C. (compound 6);

6-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,7-dimethyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one;mp. 198.2° C. (compound 7);

3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-7,8-dihydro-2-methyl-4H,6H-cyclopenta[4,5]thiazolo[3,2-a]pyrimidin-4-one;mp. 183.8°-195.8° C. (compound 8);

6-[2-[4-(4-fluorobenzoyl)-4-methyl-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-onemonohydrochloride; mp. 177.1° C. (compound 9); and6-[2-[4-(4-fluorobenzoyl)-4-phenyl-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;mp. 161.1° C. (compound 10).

EXAMPLE XV

A mixture of 3.75 parts of6-(2-chloroethyl)-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one, 3parts of 3-(4-piperidinyl)-1H-indole, 10 parts of sodium carbonate, 0.1parts of potassium iodide and 200 parts of 4-methyl-2-pentanone wasstirred and refluxed for 20 hours using a water-separator. The reactionmixture was filtered hot over Hyflo and the filtrate was evaporated. Theresidue was purified by column-chromatography over silica gel using amixture of trichloromethane and methanol (90:10 by volume) as eluent.The pure fractions were collected and the eluent was evaporated. Theresidue was crystallized from ethanol, yielding 3.25 parts of6-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one;mp. 274.7° C. (compound 11).

Following the same procedure and using equivalent amounts of theappropriate starting materials there were also prepared:

6-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;mp. 218.5° C. (compound 12);

3-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2-methyl-4H-pyrimido[2,1-b]benzothiazol-4-one;mp. 274.9° C. (compound 13);

6-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2,7-dimethyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one;mp. 260.1° C.; (compound 14);

2,3-dihydro-6-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;mp. 238.2-241.7 (dec.) (compound 15);

2-methyl-3-[2-[4-(2-methyl-1H-indol-3-yl)-1-piperidinyl]ethyl]-4H-pyrimido[2,1-b]benzothiazol-4-one;mp. 270.7° C. (compound 16);

7,8-dihydro-3-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2-methyl-4H,6H-cyclopenta[4,5]thiazolo[3,2-a]pyrimidin-4-one;mp. 242.9° C. (compound 17);

3,7-dimethyl-6-[2-[4-(2-methyl-1H-indol-3-yl)-1-piperidinyl]ethyl]-5H-thiazolo[3,2-a]pyrimidin-5-one;mp. 187.9°-188.7° C. (compound 18);

7-methyl-6-[2-[4-(2-methyl-1H-indol-3-yl)-1-piperidinyl]ethyl]-5H-thiazolo[3,2-a]pyrimidin-5-one;mp. 170.7° C. (compound 19);

6-[2-[4-(5-fluoro-1H-indol-3-yl)-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one;mp. 270.6° C. (compound 20);

6-[2-[4-(5-chloro-1H-indol-3-yl)-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;mp. 224.6° C. (compound 21);

6-[2-[4-(5-fluoro-1H-indol-3-yl)-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;mp. 244.2° C. (compound 22); and

cis-2,3-dihydro-6-[2-[4-(1H-indol-3-yl)-3-methyl-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;mp. 234.9° C. (compound 23).

EXAMPLE XVI

A mixture of 5.85 parts of6-(2-bromoethyl)-2,3,7-trimethyl-5H-thiazolo[3,2-a]pyrimidin-5-onemonohydrobromide, 4 parts of (4-fluorophenyl) (4-piperidinyl)methanonehydrochloride, 10 parts of sodium carbonate, 3 parts of a sodiummethoxide solution 30% and 240 parts of 4-methyl-2-pentanone was stirredand refluxed for 20 hours using a water-separator. The reaction mixturewas filtered hot over Hyflo and the filtrate was evaporated. The residuewas purified by column-chromatography over silica gel using a mixture oftrichloromethane and methanol (95:5 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The residue wascrystallized from a mixture of acetonitrile and 2,2'-oxybispropane (3:1by volume) yielding 1 part of6-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,3,7-trimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one;mp. 159.0° C. (compound 24).

In a similar manner there were also prepared:

6-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2,3,7-trimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one;mp. 240.2° C. (compound 25);

6-[2-[4-[(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one;mp. 138.2° C. (compound 26); and

7-[2-[4-[(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]ethyl]-3,4-dihydro-8-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one;mp. 174.1° C. (compound 27).

EXAMPLE XVII

A stirred and warm suspension of 4 parts of6-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-onein 80 parts of ethanol was acidified with phosphoric acid. 60 parts ofwater were added and the whole was boiled. The undissolved material wasfiltered off and the filtrate was allowed to crystallize. The productwas filtered off and dried, yielding 4.5 parts (80%) of6-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-onephosphate (2:3) monohydrate; mp. 214.4° C. (compound 28).

Following the same acid-addition salt formation procedure there werealso prepared:

6-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-onesulfate (1:1) monohydrate; mp. 244.3° C. (compound 29);

6-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one2-hydroxy-1,2,3-propanetricarboxylate (2:1) monohydrate; mp. 190.5° C.(compound 30).

(+)-6-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one[R-(R*,R*)]-2,3-dihydroxybutanedioate (2:1) monohydrate; mp. 177.8° C.(compound 31); and

6-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one(Z)-2-butanedioate (1:1); mp. 150.6° C. (compound 32).

EXAMPLE XVIII

A mixture of 6.8 parts of6-(2-bromoethyl)-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one,3.15 parts of α-(4-fluorophenyl)-4-piperidinemethanol, 4.8 parts ofsodium carbonate, 0.1 parts of potassium iodide and 200 parts of4-methyl-2-pentanone was stirred and refluxed for 24 hours. The reactionmixture was cooled, washed with 50 parts of water, dried, filtered andevaporated. The residue was purified by column-chromatography oversilica gel using a mixture of trichloromethane and methanol (90:10 byvolume) as eluent. The pure fractions were collected and the eluent wasevaporated. The residue solidified upon triturating in acetonitrile. Theproduct was filtered off, washed twice with acetonitrile and dried,yielding 2.5 parts (42%) of6-[2-[4-[(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]ethyl]-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;mp. 204.3° C. (compound 33).

In a similar manner there was also prepared:

cis-6-[2-[4-(1H-indol-3-yl)-3-methyl-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one; mp. 212.8° C. (compound 34).

EXAMPLE XIX

A mixture of 9.3 parts of6-(2-bromoethyl)-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-onemonohydrobromide, 6.5 parts of4-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]piperidine, 10.2 parts of sodiumcarbonate and 120 parts of 4-methyl-2-pentanone was stirred and refluxedovernight. The reaction mixture was cooled and water was added. Thelayers were separated. The organic phase was dried, filtered andevaporated. The residue was purified by column-chromatography oversilica gel using a mixture of trichloromethane and methanol (98:2 byvolume) as eluent. The pure fractions were collected and the eluent wasevaporated. The residue was crystallized from 2,2'-oxybispropane. Theproduct was filtered off and dried, yielding 4 parts (35%) of6-[2-[4-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one;mp. 140° C. (compound 35).

EXAMPLE XX

A mixture of 8.3 parts of6-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one,10 parts of 1,1',1"-[methylidynetris(oxy)]trisethane, 4 parts of4-methylbenzenesulfonic acid and 80 parts of ethanol was stirred andrefluxed for 72 hours. After cooling, gaseous ammonia was introduced.The formed precipitate was filtered off and the filtrate was evaporated.The residue was purified by column-chromatography over silica gel usinga mixture of trichloromethane and ethanol (90:10 by volume) as eluent.The pure fractions were collected and the eluent was evaporated. Theresidue was further purified by reversed phase chromatography overLiChroprep. RP 18 using a mixture of water (containing 0.5% ammoniumacetate) and methanol (containing 0.1% ofN-(1-methylethyl)-2-propanamine) (15:85 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The residue wascrystallized from 2,2'-oxybispropane, yielding 0.6 parts of 6-[2-[4-[diethoxy(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one;mp. 115.6° C. (compound 36).

What is claimed is:
 1. A chemical compound having the formula ##STR40##the pharmaceutically acceptable acid-addition salts and thestereochemically isomeric forms thereof, wherein:R¹ is hydrogen, loweralkyl or Ar; R² is hydrogen, lower alkyl or Ar; R³ is hydrogen or loweralkyl; Alk is a lower alkanediyl radical; A is a bivalent radical havingthe formula --CH₂ --CH₂ --CH₂ --, Q is a member selected from the groupconsisting of a radical having the formula --X--Ar (a) wherein X is amember selected from the group consisting of ##STR41## said q being theinteger 2 or 3; and a radical having the formula ##STR42## wherein R⁸ ishydrogen or lower alkyl and R⁹, R¹⁰ and R¹¹ are each independentlyselected from the group consisting of hydrogen and halo;wherein Ar isphenyl or substituted phenyl, said substituted phenyl bearing an aminogroup and/or 1,2 or 3 halo atoms.
 2. A chemical compound according toclaim 1 wherein R¹ is lower alkyl.
 3. A pharmaceutical composition fortreating psychotropic diseases, comprising an inert carrier and as anactive ingredient a pharmaceutically effective psychotropic amount of achemical compound selected from the group consisting of a bicyclicpyrimidin-5-one derivative having the formula ##STR43## thepharmaceutically acceptable acid-addition salts and the stereochemicallyisomeric forms thereof, wherein:R¹ is hydrogen, lower alkyl or Ar; R² ishydrogen, lower alkyl or Ar; R³ is hydrogen or lower alkyl; Alk is alower alkanediyl radical; A is a bivalent radical having the formula--CH₂ --CH₂ --CH₂ --, Q is a member selected from the group consistingof a radical having the formula --X--Ar (a) wherein X is a memberselected from the group consisting of ##STR44## said q being the integer2 or 3; and a radical having the formula ##STR45## wherein R⁸ ishydrogen or lower alkyl and R⁹, R¹⁰ and R¹¹ are each independentlyselected from the group consisting of hydrogen and halo; wherein Ar isphenyl or substituted phenyl, said substituted phenyl bearing an aminogroup and/or 1,2 or 3 halo atoms.
 4. A pharmaceutical compositionaccording to claim 3 wherein R¹ is lower alkyl.
 5. A method of treatingwarm-blooded animals suffering from psychotropic diseases whichcomprises the administration thereto of a pharmaceutically effectivepsychotropic amount of a chemical compound selected from the groupconsisting of a bicyclic pyrimidin-5-one derivative having the formula##STR46## the pharmaceutically acceptable acid-addition salts and thestereochemically isomeric forms thereof, wherein:R¹ is hydrogen, loweralkyl or Ar; R² is hydrogen, lower alkyl or Ar; R³ is hydrogen or loweralkyl; Alk is a lower alkanediyl radical; A is a bivalent radical havingthe formula --CH₂ --CH₂ --CH₂ --, Q is a member selected from the groupconsisting of a radical having the formula --X--Ar (a) wherein X is amember selected from the group consisting of ##STR47## said q being theinteger 2 or 3; and a radical having the formula ##STR48## wherein R⁸ ishydrogen or lower alkyl and R⁹, R¹⁰ and R¹¹ are each independentlyselected from the group consisting of hydrogen and halo;wherein Ar isphenyl or substituted phenyl, said substituted phenyl bearing an aminogroup and/or 1,2 or 3 halo atoms.
 6. A method according to claim 5wherein R¹ is lower alkyl.